Angiogenesis is known to exert a large influence on the wound therapy and progress of many diseases. As ophthalmic diseases involving angiogenesis, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, neovascular glaucoma and the like are known. In addition, corneal neovascularization due to various stimulations on and invasions into the cornea is also known. In these diseases, angiogenesis lacking a control mechanism occurs. Vascular endothelial growth factors (VEGF) are involved in angiogenesis, and anti-VEGF antibodies such as bevacizumab as well as sorafenib, sunitinib, pegaptanib sodium, ranibizumab, aflibercept, and VEGF-Trap EYE and the like are known as anti-VEGF drugs. Medicaments targeting VEGF are widely used clinically for the treatment of ophthalmic diseases such as age-related macular degeneration, branch retinal vein occlusion, central retinal vein occlusion, diabetic maculopathy, diabetic retinopathy, and neovascular glaucoma and the like. However, since the aforementioned anti-VEGF drugs are administered by intravitreal injection to reduce systemic side effects, a heavy burden is imposed on the patients, and the lens and retinal tissues are constantly exposed to the risk of ocular tissue damage during injection, and bacterial infection. VEGF has various activities such as maintenance of normal choroidal blood vessel homeostasis (e.g., non-patent document 1: Proc. Natl. Acad. Sci., 2009, 106: 18751-18756), action as a nutritional factor of retinal nerve cells (e.g., non-patent document 2: Am. J. Patho., 2007, 171: 53-67) and the like, and the possibility that a long-term inhibition of VEGF may provide an adverse influence on the ocular tissues cannot be denied. Therefore, the development of a treatment method targeting a molecule other than VEGF and selectively effective for angiogenesis is one of the problems. In recent years, it is known that chemokine, which is one of the cell chemotactic factors, induces angiogenesis (non-patent document 3: Arterioscler. Thromb. Vasc. Biol., 2008, 28: 1928-1936). Particularly, CCL11 in the CC chemokine family is known to induce migration of vascular endothelial cells and angiogenesis in vivo model, by a signal via CCR3, which is a receptor thereof (non-patent document 4: J. Immunology, 2001, 166: 7571-7578). CCR3 is known as a chemokine receptor of eosinophils, and antagonists thereof have been studied as treatment targets of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis (non-patent document 5: Medicinal Research Reviews, 2010, 30: 778-817). However, it has been clarified that CCR3 is specifically expressed in vascular endothelial cells of choroidal new blood vessels with age-related macular degeneration, and involved in the progress thereof (non-patent document 6: Nature, 2009, 460: 225-230). In addition, a patent application describing that 4-[[[[[[(2S)-4-[(3,4-dichlorophenyl)methyl]-2-morpholinyl]methyl]-amino]carbonyl]amino]methyl]benzamide, which is a CCR3 antagonist, is useful for neovascular age related macular degeneration has been published (patent document 1: WO 2013/079696). In addition, it has been reported that expression of CCR3 is found in choroidal vascular endothelial cells in choroidal neovascularization found in eye histoplasmosis syndrome (non-patent document 7: Invest. Ophthalmol. Vis. Sci., 2010, 51: E-Abstract 3351), and expression of CCR3 is found in the corneal neovascularization site of a corneal neovascularization model due to corneal injury (non-patent document 8: Int. J. Ophthalmol., 2012, 5: 251-257). Furthermore, it has been recently reported that CCR3 is expressed in the vascular endothelium of a proliferative membrane isolated from proliferative diabetic retinopathy (non-patent document 9: Japanese Journal of Ophthalmology 2013 vol. 117, Extra issue, Abstract No. P-140). Therefore, a low-molecular-weight compound showing a CCR3 antagonistic action can treat and/or prevent ocular angiogenesis by a mechanism different from that of an anti-VEGF drug.
On the other hand, a morpholine compound represented by the following formula (1)
[whereinring A is aryl optionally having substituent(s), or heteroaryl optionally having substituent(s),ring B is arylene optionally having substituent(s), a divalent heterocyclic group optionally having substituent(s), or C3-8 cycloalkylene optionally having substituent(s),m is an integer of 0 to 2,n is an integer of 1 to 5,X is a bond, —NH—, —NR1— (wherein R1 is C1-6 alkyl optionally having substituent(s)), —CO—, —CO2—, —OCO—, —CONRa— (wherein Ra is a hydrogen atom or C1-6 alkyl optionally having substituent(s), hereinafter the same), —NRaCO—, —NR2CONR3— (wherein R2 and R3 are the same or different and each is a hydrogen atom or C1-6 alkyl optionally having substituent(s), or R2 and R3 are optionally joined to form, together with atoms bonded thereto, a ring optionally having substituent(s)), an oxygen atom, a sulfur atom, —SO—, —SO2—, —NRaSO2—, —SO2NRa—, C1-6 alkylene optionally having substituent(s), C2-6 alkenylene optionally having substituent(s), C2-6 alkynylene optionally having substituent(s), —O—Xa— (wherein Xa is C1-6 alkylene optionally having substituent(s), hereinafter the same), —Xa—O—, —CO—Xa—, —Xa—CO—, —CONRa—Xa—, —Xa—CONRa—, —NRaCO—Xa—, —Xa—NRaCO—, —S—Xa—, —Xa—S—, —SO—Xa—, —Xa—SO—, —NRa—Xa—, —Xa—NRa—, —SO2—Xa—, —Xa—SO2—, —C(═N—CO2—R1)—, —C(═N—SO2—R1)—, —C(═N—SO2NH2)—, —C(═CH—NO2)—, —C(═N—CN)— or C3-8 cycloalkylidene optionally having substituent(s),Y is a bond, —NH—, —NR4— (wherein R4 is C1-6 alkyl optionally having substituent(s), hereinafter the same), —CO—, —CO2—, —OCO—, —CONRb— (wherein Rb is a hydrogen atom or C1-6 alkyl optionally having substituent(s), hereinafter the same), —NRbCO—, —NR5CONR6— (wherein R5 and R6 are the same or different and each is a hydrogen atom or C1-6 alkyl optionally having substituent(s), or R5 and R6 are optionally joined to form, together with atoms bonded thereto, a ring optionally having substituent(s)), an oxygen atom, a sulfur atom, —SO—, —SO2—, —NRbSO2—, —SO2NRb—, C1-6 alkylene optionally having substituent(s), C2-6 alkenylene optionally having substituent(s), C2-6 alkynylene optionally having substituent(s), —O—Xb— (wherein Xb is C1-6 alkylene optionally having substituent(s), hereinafter the same), —Xb—O—, —CO—Xb—, —Xb—CO—, —CONRb—Xb—, —Xb—CONRb—, —NRbCO—Xb—, —Xb—NRbCO—, —S—Xb—, —Xb—S—, —SO—Xb—, —Xb—SO—, —NRb—Xb—, —Xb—NRb—, —SO2—Xb—, —Xb—SO2—, —C(═N—CO2—R4)—, —C(═N—SO2—R4)—, —C(═N—SO2NH2)—, —C(═CH—NO2)— or —C(═N—CN)—, andZ is a hydrogen atom, a halogen atom, C1-6 alkyl optionally having substituent(s), C3-8 cycloalkyl optionally having substituent(s), aryl optionally having substituent(s), a heterocyclic group optionally having substituent(s), hydroxy, nitro, amino, cyano, C1-6 alkoxy optionally having substituent(s), mono- or di-C1-6 alkylamino optionally having substituent(s), C1-7 acylamino optionally having substituent(s), sulfonylamino optionally having substituent(s), hydrazino optionally having substituent(s), guanidino optionally having substituent(s) or amidino optionally having substituent(s)], or a pharmaceutically acceptable salt thereof is a compound having a CCR3 antagonistic action, which is described in WO pamphlets of WO 2006/028284 (patent document 2) and WO 2008/007691 (patent document 3). However, there is no prior art document that describes or suggests that such morpholine compound treats and/or prevents ocular angiogenesis.